A group of researchers at the Howard Hughes Medical Institute and Center for Neurobiology and Behavior has identified a protein that blocks the formation of long-term memories. As described in a study published in a December issue of Cell, the protein, ApCREB2, was identified in the marine snail Aplysia californica but is similar to the protein CREB2 in humans. This research was carried out by Dusan Bartsch and Mirella
Ghirardi, two postdoctoral fellows in the laboratory of Dr. Eric Kandel.

In previous work, the researchers found that the conversion of short-term memories into long-term ones involves the activation of certain genes, says Dr. Kandel, University Professor in the Department of Biochemistry and Molecular Biophysics and in the Center for Neurobiology and Behavior. So far, they have found three proteins that activate this long-term memory gene "switch." CREB2, however, is the first protein that represses the switch.

"This is a clue that long-term memory may be regulated at the very first step," says Dr. Kandel. "There may be a threshold for long-term memory that is controlled by repressors." With CREB2 present, it takes repeated signals to activator proteins to switch on long-term memory. Without CREB2, just one signal is sufficient to produce long-term memory on the cellular level.

The findings provide potential clues into the mechanisms that might be important to human memory. Memory loss due to aging, for example, is characterized by the inability to consolidate long-term memories. This may be the result in part of either a lack of activating proteins or an inability to relieve the action of repressor proteins.

Furthermore, the phenomenon of photographic memory, or similar unusual memory abilities, could be due to an inherited imbalance of repressor vs. activator proteins.
"Flashbulb memories"-the vivid recollection of emotionally significant, shocking, or traumatic events-also may be governed by repressors. These memories may occur because the emotional stress "primes" the system to store a long-term memory by removing the repressor. Thus, for example, most people remember years later where they were and what they were doing when President Kennedy was assassinated or when the space shuttle Challenger exploded.

The repressor/activator system raises the possibility of drugs that may treat a range of memory problems by acting on this regulation point.